WO2019038110A1

WO2019038110A1 - Mouthwash containing octenidine hydrochloride

Info

Publication number: WO2019038110A1
Application number: PCT/EP2018/071817
Authority: WO
Inventors: Sabine Behrends; Thomas Spuida; Andreas Dettmann
Original assignee: Schülke & Mayr GmbH
Priority date: 2017-08-23
Filing date: 2018-08-10
Publication date: 2019-02-28
Also published as: SG11202001406WA; DE102017119261A1; EP3672569A1; AU2018322279A1

Abstract

The present invention relates to an aqueous composition which contains octenidine dihydrochloride. The composition is preferably used as mouthwash or oromucosal solution.

Description

Mouthwash Containing Octenidine Hydrochloride

The present invention relates to an aqueous composition which contains octenidine dihydrochloride . The composition is preferably used as a mouthwash or oromucosal solution (solution for use in the oral cavity) , for i) transient germ count reduction in the oral space, ii) inhibition of plaque formation iii) in case of limited oral hygiene capability. DE 10 2006 051 891 Al discloses a water-based antimicrobially active composition which contains a bispyridinium alkane (such as octenidine dihydrochloride, also referred to below as "octenidine") , and the use of the composition as a mouth rinse solution or oral antiseptic. Compositions given as examples have a pH of 4 and have good activity in the quantitative suspension experiment with E. faecalis (ATCC 19433) and in the quantitative suspension experiment with various MRSA isolates under dirty conditions . In addition, some formulations in DE 10 2006 051 891 Al contain phenoxyethanol . A disadvantage with phenoxyethanol is the furry taste.

For a pleasant taste, in DE 10 2006 051 891 Al it is for example proposed to use aspartame as a sweetener. If one now attempts, starting from this teaching, to further improve the taste or the compositions of DE 10 2006 051 891 Al, for example by increasing the quantity of flavouring used, the quantity of sweetener must also be increased, and, in order to increase the storage stability, also the quantity of emulsifier. However, it has been found than an increased quantity of emulsifier decreases the antimicrobial activity of compositions with a content of octenidine.

DE 10 2008 011 691 A discloses a stabilized antimicrobially active water-based composition which contains a bispyridinium alkane, and use of the composition for the production of microbicidally active cosmetic and pharmaceutical preparations and for the production of microbicidally equipped articles. As stabilizers, antioxidants, complexing agents, reducing agents, UV filters and light stabilizers are proposed. Application solutions described in DE 10 2008 011 691 A contain aspartame as sweetener and in the presence of DL- -tocopherol are storage stable even on storage at 40°C over a period of six months (i.e. no formation of aldehydes or peroxides is observed) .

DE 10 2005 045 146 A discloses antimicrobial compositions which contain octenidine encapsulated in liposomes. DE 196 47 692 A discloses a disinfecting composition which contains octenidine, Ci to Cs alkyl alcohol, nonionic and/or cationic surfactant and skin-compatible a-hydroxycarboxylic acid.

The present invention was based on the objective of providing aqueous compositions based on the active substance octenidine, which on the one hand are pleasant in taste (i.e. in which the bitter intrinsic taste of octenidine is not apparent) , which however on the other hand contain as few as possible additives which are not necessary for the antimicrobial action and the taste. The compositions should nonetheless exhibit very good storage stability.

It has now surprisingly been found that this problem is solved by an aqueous composition which contains

a) 0.07 to 0.13 wt . % octenidine dihydrochloride, b) 1.0 to 2.5 wt . % fatty acid monoglyceride substituted with 20 to 70 alkoxy groups,

c) 0.3 to 0.6 wt . % glycerine,

d) gluconic acid or gluconic acid salt, in a quantity of 0.2 to 0.6 wt.%, stated as sodium gluconate, e) 0.03 to 0.2 wt.% sucralose, f) citric acid or citric acid salt, in a quantity of 0.05 to 0.15 wt.-%, stated as citric acid (anhydrous) ,

g) flavouring and

h) buffer.

The composition according to the invention has a pH in the range from 5.0 to 7.0 and contains no aspartame. In addition, the aqueous composition according to the invention is a clear solution. This solution is characterized by good antimicrobial activity, good storage stability and a pleasant taste.

According to a first aspect, the invention thus relates to the aqueous composition. According to a second aspect, the invention relates to use of the aqueous composition as a mouthwash or oromucosal solution.

The aqueous composition according to the invention according to the first aspect contains

c) 0.3 to 0.6 wt . % glycerine,

d) gluconic acid or gluconic acid salt, in a quantity of 0.2 to 0.6 wt.%, stated as sodium gluconate, e) 0.03 to 0.2 wt.% sucralose,

f) citric acid or citric acid salt, in a quantity of 0.05 to 0.15 wt.%, stated as citric acid (anhydrous) ,

g) flavouring and

h) buffer,

wherein the composition

- has a pH in the range from 5.0 to 7.0 and

- contains no aspartame. The quantity of component a) is preferably 0.08 to 0.12 wt.%, more preferably 0.09 to 0.11 wt.%, in particular about 0.1 wt . % . The quantity of component b) is preferably 1.5 to 2.0 wt . ~6 , in particular about 1.75 wt.%.

The fatty acid monoglyceride substituted with 20 to 70 alkoxy groups is preferably fatty acid monoglyceride substituted with 20 to 70 ethoxy groups, in particular glycerol hydroxystearate substituted with 40 ethylene oxide units.

The quantity of component c) is preferably 0.35 to 0.5 wt.%, more preferably 0.4 to 0.45 wt.%, in particular about 0.425 wt.%.

The quantity of component d) is preferably 0.3 to 0.5 wt.%, more preferably 0.35 to 0.45 wt.%, in particular about 0.4 wt . % .

The quantity of component e) is preferably 0.05 to 0.15 wt.%, more preferably 0.07 to 0.13 wt.%, in particular about 0.1 wt . % . The quantity of component f) is preferably 0.07 to 0.11 wt.%, 0.08 to 0.1 wt.%, in particular about 0.09 wt.%.

The quantity of component g) is preferably 0.1 to 1.0 wt.%, more preferably 0.2 to 0.8 wt.-%, in particular about 0.5 wt.%.

The flavouring g) is preferably selected from

gl) a mixture of menthol with menthone,

g2) strawberry flavouring,

g3) banana flavouring and

g4) cherry flavouring,

or a mixture of two or more thereof. The buffer h) is preferably a phosphate buffer.

Preferably the composition contains less than 1 wt . % phenoxyethanol , more preferably less than 1 wt . % aromatic alcohol, in particular less than 0.5 wt . % aromatic alcohol, with the composition particularly preferably being free from aromatic alcohol. More preferably the composition contains no tocopherol and no derivative thereof, wherein the composition in particular contains no tocopherol, no derivative thereof and no BHT (butylhydroxytoluene) . Preferably compositions according to the invention are free from alpha-tocopherol , BHT, tocopherol acetate, BHA (butyl- hydroxyanisole) , dodecyl gallate or ascorbic acid, and preferably contain none of these components. The composition according to the invention is preferably used as a mouthwash or oromucosal solution for i) transient microbial count reduction in the oral space, ii) inhibition of plaque formation or iii) in case of limited oral hygiene capability .

The advantages of the present invention follow in particular from the following examples. Unless otherwise stated, percentage information relates to weight. Examples

Example 1 - Unsatisfactory taste of compositions with a rather low content of aspartame

In a formulation based on octenidine, the quantities of flavouring and sweetener and the flavouring types should be matched. The components are stated in Table 1. Table 1. Formulations tested in example

The formulations A to E were compared by taste (Table

Table 2. Taste comparison of the formulations tested in example 1

The results show that with a moderate content of aspartame it is not possible to create a pleasant taste in octenidine- containing compositions.

Example 2 - Storage stability of a formulation with aspartame In the following experiments the storage stability of a formulation with aspartame was tested (Table 3) . Table 3. Formulation tested in example

Water 97.60

Octenidine dihydrochloride 0.10

Glycerol 85% 0.50

Sodium gluconate 0.40

Cremophor RH 40 1.00

Flavour Mint Cool 0.25

Aspartame powder 0.15

Citric acid to pH 4.0

100.00

Table 4. Storage stability of a formulation with aspartame

*= additional peaks appeared Hazen = Hazen colour number NTU = turbidity measurement

The data confirm the unsatisfactory storage stability of octenidine-containing formulations with the sweetener aspartame, even when formulated at the pH of about 4 recommended for aspartame for optimal stability.

Example 3 - Storage stability of a formulation without aspartame

In the following experiments, a formulation with 0.2% octenidine and with a high content of nonionic surfactant was tested so as to be able to better simulate the decomposition.

In Tables 5 and 6, the contents of octenidine and two known decomposition products (keto compound and imino compound) are stated. The aqueous formulations A to M were tested, each with 0.2% octenidine dihydrochloride and addition of 0.1% citric acid monohydrate, and 1) emulsifier (macrogol glycerol hydroxystearate-40EO) and 2) the stated agents for adjustment of the pH (NaOH = 5% aqueous sodium hydroxide, phosphate = Na₂HP0₄*2H₂0) .

Table 5. Stability test 3 months, unopened bottles 250 ml (Mo = month (s) )

Table 6. Stability test 6 months, bottles opened once, 250 ml

Example 4

Formulations I to VII and IX to XI

The purpose of this formula validation was to find out what effect the concentration of the emulsifier (Cremophor RH 40) and a change in the pH have on the product stability and on its antimicrobial activity.

The emulsifier content was studied around the actual value of 1.75% in a bandwidth from 1.0% to 2.0%. These experiments took place at the average octenidine dihydrochloride concentration (0.15%) .

The pH was studied around the currently envisaged shelf life specification from 5.5 to 6.3 at the low limit of 5.4 and the upper limit of 6.4. In this, the highest octenidine dihydrochloride concentration (0.2%) was tested at both pH extremes, but on the other hand the lowest octenidine dihydrochloride concentration (0.1%) only at the lower pH limit (Table 7) .

Table 7

Test to be

0.10% 0.15% 0.20%

performed

Octenidine Octenidine Octenidine

Effect of pH Stability (shelf life test with pH specification measurement,

6.4 -- 5.4 + 6.4

5.5-6.3) pH in vitro 5.4 and pH activity 6.4 testing

Stability

Effect of test with emulsifier physical (Cremophor RH data,

40) 1.0%, -- X -- appearance in 1 · 25"6 _/ 1. -6_/ refrigerator, 1.6-6_/ 1.75-6_/ in vitro 1.9%, 2.0% activity testing The following materials were used (Table 8) :

Table 8

The following compositions were formulated (Table 9) :

Table 9

For the formulations I to VII, in the context of a stability test, physical and chemical data were determined, and a study of the antimicrobial activity and an optical assessment of the refrigerator samples performed.

For the stability testing, under the conditions +25°C and +40°C (not ICH conditions), the bottles (250 ml, PET) were stored as follows:

+25°C (ca. 35% RH) ,

+40°C (ca. 12% RH) ,

and in the refrigerator: ca. +3°C to +8°C (no temperature recording, only visual inspection) .

After 4 weeks, the following parameters were studied for all samples. The visual assessment of the samples which were stored in the refrigerator in each case took place after 1, 2, 3, 4, 7, 10, 17, 24 and 28 days.

For the formulations IX, X and XI (test samples for effect of pH) , the stability of the pH was studied and additionally for the formulae X and XI the antimicrobial activity during storage .

For the stability testing under the conditions +25°C and +40°C in the stability rooms of F+E (not ICH conditions) , the bottles (250 ml, PET) were stored as follows:

+25°C (ca. 35% RH) ,

+40°C (ca. 12% RH) ,

and in the refrigerator:

ca. +3°C to +8°C (no temperature recording).

After 6 weeks the pH of all samples was studied (Table 10) .

Table 10.

= Method not validated, presumable LOD for degradation oducts: 4 ppm

1 Effect of emulsifier content, formulations I to VII: a) Physical and chemical data (at start and after 4 weeks storage) : Tab e 11

b) Optical assessment (over 28 days storage) , Table (n.c. = no change)

(Day 1)

25°C 40°C 3-8°C

I

II

III

IV n.c. n.c. n.c.

V

VI

VII

(Day 2) :

25°C 40°C 3-8°C

very many

I crystals

rather more

II crystals than

in III

n.c. n.c. first small

III crystals

IV n.c.

V n.c.

VI n.c.

VII n.c.

(Day 3) :

25°C 40°C 3-8°C

very many

n.c. n.c.

I crystals

isolated

III crystals

IV n.c.

V n.c.

VI n.c.

VII n.c. (Day 4) :

25°C 40°C 3-8°C

very many

I crystals a few large

II crystals isolated n . c . n . c .

III crystals

IV n . c .

V n . c .

VI n . c .

VII n . c .

(Day 7) :

25°C 40°C 3-8°C

very many

I crystals a few large

II crystals isolated n . c . n . c .

III crystals

IV n . c .

V n . c .

VI n . c .

VII n . c .

(Day 10) :

25°C 40°C 3-8°C

very many

I crystals very many

II crystals

III n . c . n . c . many crystals

IV n . c .

V n . c .

VI n . c .

VII n . c .

(Day 17) :

25°C 40°C 3-8°C

very many

I crystals very many

II crystals

III n . c . n . c . many crystals

IV n . c .

V n . c .

VI n . c .

VII n . c . (Day 24) :

Assessment of the physical and chemical and optical data for I to VII:

After 4 weeks storage with all formulations no significant changes in the physical and chemical properties are seen.

In the optical examination, in the samples which were stored at +25°C and +40°C, no visible abnormalities were found after 6 weeks storage.

On the other hand, in the samples which had been stored in the refrigerator, it is found that an emulsifier content of at least 1.6% (formulation IV) is advantageous for adequate solubilization to ensure stability as regards precipitates / crystallization effects. All formulations with lower additions of emulsifier already show signs of precipitates after short-term cold storage of only 2 days. Based on the above precipitation findings, it follows that the minimum emulsifier content to ensure the physical stability of the product solution is 1.6%, on the basis of which, with a safety increment of rel. 10%, the current emulsifier actual content of 1.75% is to be regarded as appropriate . c) Results of the studies on the antimicrobial activity in vitro :

In order to investigate a possible effect of the emulsifier content (Cremophor RH 40) on the antimicrobial activity, quantitative suspension experiments according to EN 13727 (Staphylococcus aureus ATCC 6538 and Pseudomonas aeruginosa ATCC 15442) and EN 13624 (Candida albicans ATCC 10231) were each performed on the formulation with average active substance concentration (0.15%). The following values were determined for Candida albicans (Table 12) :

Table 12

Emulsifier Exposure Exposure content time time

30 seconds 60 seconds

I 1.0% >4.38 >4.38

II 1.25% >4.38 >4.38

III 1.4% 3.76 >4.38

IV 1.6% 3.65 >4.38

V 1.9% 2.42 3.51

VI 2.0% 1.38 2.78

VII 1.75% 2.22 3.97 The following values were determined for Staphylococcus aureus (Table 13) :

Table 13

The following values were determined for Pseudomonas aeruginosa (Table 14) :

Table 14

Assessment of the antimicrobial activity of Formulae I to VII

From the above results it is clear that higher emulsifier concentrations cause a reduction in the in vitro antimicrobial activity, particularly pronounced at the highest tested used concentration of 2.0%, at shorter exposure times.

In comparison to the formulae with lower emulsifier content, the in vitro antimicrobial activity of the currently intended formulation using 1.75% emulsifier seems to be slightly reduced sometimes, but overall is to be regarded as adequate. Based on indications of a significantly worse antimicrobial performance of the formulation with addition of 2.0% emulsifier, an increase in the addition of emulsifier above the 1.75% necessary for physical stabilization cannot be justified.

Example 3.2 Effect of the pH, formulations IX-XI a) pH stability (initially and after 6 weeks storage)

Table 15

Assessment of the pH stability

After 6 weeks storage at the storage temperatures +25 and +40°C and in the refrigerator at +3 to +8°C, no significant changes in the pH are seen. b) Results in the studies of antimicrobial activity in vi tro

In order to investigate a possible effect of the pH on the antimicrobial activity, quantitative suspension experiments according to EN 13727 (Staphylococcus aureus and Pseudomonas aeruginosa) and EN 13624 [Candida albicans) were each performed with the preparations mentioned below.

The following values were determined for Candida albicans (Table 16) :

Table 16

Lab. No. Oct . pH Exposure Exposure

cone . time time

30 seconds 60 seconds

II 0.2% 5.4 >4.38 >4.38

III 0.2% 6.4 3.76 >4.38 The following values were determined for Staphylococcus aureus (Table 17) :

Table 17

The following values were determined for Pseudomonas aeruginosa (Table 18) :

Table 18

Assessment of the antimicrobial activity depending on the pH

From the above results it can be clearly seen that the 0.2% formulations at the pH specification limits of pH 5.4 and pH 6.4 show no significant differences in the in vitro antimicrobial activity. On this basis, the desired tolerance range from pH 5.5 - 6.3 for the shelf life specification can be regarded as confirmed.

Example 3.3 Overall assessment and conclusion

The results of this formulation study confirm that the emulsifier content of 1.75% is necessary to ensure the physical stability of the solution with regard to precipitates and crystallization effects; because of an adverse effect of increasing emulsifier concentration on the in vitro antimicrobial activity, a further increase in the quantity added is not justifiable. Over the confirmed storage time of 4 weeks, the other physical and chemical properties under all storage conditions (refrigerator, 25°C and 40°C) do not show a different shelf- life behaviour depending on emulsifier quantity added.

Within the desired tolerance range from pH 5.5 - 6.3, a significant effect of the pH on the antimicrobial activity of the desired formulation can be ruled out on the basis of the in vitro activity measurements. In addition, the studies confirm the stability of the pH values at the lower and upper limit of the tolerance range on 6 weeks storage under all confirmed storage conditions (refrigerator, 25°C and 40°C).

Claims

Aqueous composition which contains

c) 0.3 to 0.6 wt . % glycerine,

d) gluconic acid or gluconic acid salt, in a quantity of 0.2 to 0.6 wt.%, stated as sodium gluconate,

e) 0.03 to 0.2 wt.% sucralose,

g) flavouring and

h) buffer,

wherein the solution

has a pH in the range from 5.0 to 7.0 and

contains no aspartame.

Composition according to Claim 1, characterized in that the quantity of component a) is 0.08 to 0.12 wt.%, preferably 0.09 to 0.11 wt.%, in particular about 0.1 wt . % .

Composition according to Claim 1 or 2, characterized in that the quantity of component b) is 1.5 to 2.0 wt.%, in particular about 1.75 wt.%.

Composition according to one of the previous Claims, characterized in that the fatty acid monoglyceride substituted with 20 to 70 alkoxy groups is fatty acid monoglyceride substituted with 20 to 70 ethoxy groups, in particular glycerol hydroxystearate substituted with 40 ethylene oxide units.

5. Composition according to one of the previous Claims, characterized in that the quantity of component c) is 0.35 to 0.5 wt.%, preferably 0.4 to 0.45 wt.%, in particular about 0.425 wt.%.

6. Composition according to one of the previous Claims, characterized in that the quantity of component d) is 0.3 to 0.5 wt.%, preferably 0.35 to 0.45 wt . ~6 , in particular about 0.4 wt.%.

7. Composition according to one of the previous Claims, characterized in that the quantity of component e) is 0.05 to 0.15 wt.%, preferably 0.07 to 0.13 wt.%, in particular about 0.1 wt.%.

8. Composition according to one of the previous Claims, characterized in that the quantity of component f) is 0.07 to 0.11 wt.%, preferably 0.08 to 0.1 wt.%, in particular about 0.09 wt.%.

9. Composition according to one of the previous Claims, characterized in that the quantity of component g) is 0.1 to 1.0 wt.%, preferably 0.2 to 0.8 wt . ~6 , in particular about 0.5 wt.%.

10. Composition according to one of the previous Claims, characterized in that the buffer is a phosphate buffer.

11. Composition according to one of the previous Claims, characterized in that it contains less than 1 wt.% phenoxyethanol , preferably less than 1 wt.% aromatic alcohol, in particular less than 0.5 wt.% aromatic alcohol, wherein the composition especially preferably is free from aromatic alcohol.

12. Composition according to one of the previous Claims, characterized in that it contains no tocopherol and no derivative thereof, wherein the composition contains no tocopherol, no derivative thereof and no BH .

13. Use of the composition according to one of the previous claims as mouthwash or oromucosal solution.

14. Use of the composition according to Claim 13, for i) transient microbial count reduction in the oral cavity, ii) inhibition of plaque formation or iii) in case of limited oral hygiene capability.